NKT cells control tumor associated macrophages and metastatic growth in neuroblastoma
Amy N. Courtney, Gengwen Tian, Ekaterina Marinova, Jie Wei, Linjie Guo, Jingling Jin, Xiuhua Gao, Ketan B. Ghaghada*, Leonid S. Metelitsa
Dept. of Pediatrics, and *Dept. of Pediatric Radiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX, 77030
Va24-invariant NKT cells (NKTs) control tumor growth via poorly understood interactions with CD1d-positive tumor-associated macrophages (TAMs). TAMs comprise M1- and M2-like subsets, but only CD163high M2-like TAMs are associated with poor outcome in neuroblastoma (NB) patients. Here, we demonstrate that NKTs selectively target M2-like TAMs via contact-dependent and independent mechanisms. Upon direct contact with antigen-pulsed M1 or M2, NKTs selectively kill the latter. Additionally, we found that antigen-activated NKTs could reprogram M2 into functional M1-like macrophages via GM-CSF production. Furthermore, adoptive transfer of human NKTs resulted in M1-like polarization of TAMs in metastatic NB xenografts in humanized NSG mice. To further explore the role of NKT–TAM axis in tumor immune surveillance, we examined the effect of NKT deficiency on tumor progression and TAM accumulation in NB-Tag transgenic model of NB. Mice lacking either type I (Jα18-/-NB-Tag) or all (CD1d-/-NB-Tag) NKTs had shortened survival compared with NB-Tag mice (P < 0.0002). At four month of age we observed an increase of CD11b+Ly6G-Ly6C-F4/80+ TAMs in primary tumors of NKT deficient groups compared with NB-Tag mice. Despite no difference in the size of primary adrenal tumors between groups, the increase of TAM frequency coincided with metastatic spread in NKT-cell deficient groups as detected by computed tomography (CT) imaging and confirmed by pathological analysis. By five months, nearly all mice in NKT-cell deficient groups had distant metastases in liver and lungs but none of the NKT-cell replete mice had detectable distant metastases. Thus, our results reveal a novel mechanism of immune regulation, in which NKTs selectively control M2-like TAMs and suppress tumor metastasis.
Supported by NIH/NCI 2RO1 CA116548.